Pannexin-1 modulates short-term synaptic plasticity by facilitating endocannabinoid transport
Abstract
Pannexin-1 (Panx1) is a large pore ion/metabolite channel that is permeable to various molecules, ions, ATP, signaling lipids, and fluorescent dyes. To date, Panx1 has been implicated in many pathological conditions including ischemia, epilepsy, cancer, and inflammation. Ascribing a physiological function for these channels in the brain remains elusive outside of reported involvement in modulating synaptic plasticity in the form of long-term potentiation and long-term depression. The mechanisms by which Panx1 contributes to synaptic physiology are largely unknown. Its high expression in many brain regions (including the hippocampus), postsynaptic localization, ability to release ATP, and coupling to glutamate- sensitive NMDAR receptors make Panx1 a great candidate for altering neurotransmission. As such, this thesis explores the role of Panx1 in synaptic plasticity and its underlying signaling mechanisms. My overarching hypothesis is that Panx1 function is critical in maintaining homeostatic neural signaling and that interruption of Panx1 function can result in pathological outcomes. Here I show that inhibition of Panx1 alters neurotransmission in the hippocampus at both inhibitory and excitatory synapses due to its actions as a transporter of the endocannabinoid/ endovanilloid, anandamide (AEA). Regulation of synaptic AEA concentrations is critical to homeostatic control of neurotransmitter release since AEA can act both at CB1Rs, to depress neurotransmission, and TRPV1 channels, to enhance glutamate release. I demonstrate that Panx1 can permeate AEA and alter synaptic AEA concentration, which results in interruption of canonical AEA signaling at CB1Rs. In vivo, this change in AEA concentration leads to neuronal hyper-excitability demonstrated as a heightened rate of seizure susceptibility. In conclusion, the research in this thesis provides a novel role of Panx1 as a transporter of AEA, which may have broad implications in several disease states where AEA dysregulation contributes to pathophysiology.
Description
Keywords
Neuroscience
Citation
Bialecki, J. (2017). Pannexin-1 modulates short-term synaptic plasticity by facilitating endocannabinoid transport (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/27251